Preparation of carbocyclic compounds

ABSTRACT

The present invention provides new synthetic methods and compositions. In particular, new methods of preparing intermediates useful in the synthesis of neuraminidase inhibitors and compositions useful as intermediates that are themselves useful in the synthesis of neuraminidase inhibitors are provided.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to methods of preparing carbocycliccompounds and intermediates therefore.

2. Brief Description of Related Art

U.S. patent application Ser. No. 08/702,308, filed Aug. 23, 1996, whichwas a continuation-in-part application of U.S. patent application Ser.No. 08/653,034, filed Mar. 24, 1996, which was a continuation-in-partapplication of U.S. patent application Ser. No. 08/606,624, filed Feb.26, 1996, which was a continuation-in-part application of U.S. patentapplication Ser. No. 08/580,567, filed Dec. 29, 1995, which was acontinuation-in-part application of U.S. patent application Ser. No.08/476,946, filed Jun. 6, 1995, which was a continuation-in-partapplication of U.S. patent application Ser. No. 08/395,245, filed Feb.27, 1995, all of which are incorporated herein by reference in theirentirety, describe, inter alia neuraminadase inhibitors andintermediates in the synthesis of neuraminidase inhibitor. The presentinvention provides processes useful in the preparation of thesecompositions.

OBJECTS OF THE INVENTION

Selected embodiments of the invention are directed to one or more of thefollowing objects:

A principal object of the invention is to provide new synthetic methodsand compositions.

An additional object of the invention is to provide new methods ofpreparing intermediates useful in the synthesis of neuraminidaseinhibitors.

An additional object of the invention is to provide compositions usefulas intermediates that are themselves useful in the synthesis ofneuraminidase inhibitors.

An additional object of the invention is to provide compositions usefulas neuraminidase inhibitors.

SUMMARY OF THE INVENTION

One aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR1## wherein: R¹ is acyclic hydroxy protecting group;

R² is a carboxylic acid protecting group;

R³ is a hydroxy protecting group; and

each R²⁰ is independently H or an alkyl of 1 to 12 carbon atoms;

which process comprises reaction of a compound of the formula: ##STR2##with a dehydrating reagent.

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR3## wherein: each of R²,R³ and R²⁰ are as defined above;

R⁴ is --C(R³⁰)₃ ;

each R⁵ is independently H or R³ ;

each R⁷ is independently H or an amino protecting group;

each R⁸ is independently H or R² ;

each R⁹ is independently H or a thiol protecting group;

each R²¹ is independently R²⁰, Br, Cl, F, I, CN, NO₂ or N₃ ;

each R²² is independently F, Cl, Br, I, --CN, N₃, --NO₂, --OR⁵, --OR²⁰,--N(R²⁰)₂, --N(R²⁰)(R⁷), --N(R⁷)₂, --SR²⁰, --SR⁹, --S(O)R²⁰, --S(O)₂R²⁰, --S(O)OR²⁰, --S(O)OR⁸, --S(O)₂ OR²⁰, --S(O)₂ OR⁸, --C(O)OR²⁰,--C(O)OR⁸, --OC(O)R²⁰, --N(R²⁰)(C(O)R²⁰), --N(R⁷)(C(O)R²⁰),--N(R²⁰)(C(O)OR²⁰), --N(R⁷)(C(O)OR²⁰), --C(O)N(R²⁰)₂, --C(O)N(R⁷)(R²⁰),--C(O)N(R⁷)₂, --C(NR²⁰)(N(R²⁰)₂), --C(N(R⁷))(N(R²⁰)₂),--C(N(R²⁰))(N(R²⁰)(R⁷)), --C(N(R⁷))(N(R²⁰)(R.sup.7)),--C(N(R²⁰))(N(R⁷)₂), --C(N(R⁷))(N(R⁷)₂₀), --N(R²⁰)C(N(R²⁰))(N(R²)₂),--N(R²⁰)C(N(R²⁰))(N(R²⁰)(R⁷)), --N(R²⁰)C(N(R⁷))(N(R²⁰)₂),--N(R⁷)C(N(R²⁰))(N(R²⁰)₂), --N(R⁷)C(N(R⁷))(N(R²⁰)₂),--N(R⁷)C(N(R²⁰))(N(R²⁰)(R⁷)), --N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)),--N(R²⁰)C(N(R²⁰))(N(R⁷)₂), --N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)),--N(R⁷)C(N(R²⁰))(N(R⁷)₂), --N(R²⁰)C(N(R⁷))(N(R⁷)₂),--N(R⁷)C(N(R⁷))(N(R⁷)₂), ═O, ═S, ═N(R²⁰), ═N(R⁷) or W;

each R²³ is independently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to11 carbon atoms, or alkynyl of 2 to 11 carbon atoms;

each R²⁴ is independently R²³ wherein each R²³ is substituted with 0 to3 R²² groups;

each R^(24a) is independently alkylene of 1 to 11 carbon atoms,alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atomsany one of which alkylene, alkenylene or alkynylene is substituted with0-3 R²² groups; compound;

each R²⁸ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;

each R²⁹ is independently R²² or R²⁸ wherein each R²⁸ is substitutedwith 0 to 3 R²² groups;

each R³⁰ is independently H, R²⁴, W or --R^(24a) W; and

each W is independently carbocycle or heterocycle wherein any one ofwhich carbocycle or heterocycle is substituted with 0 to 3 R²⁹ groups;

which process comprises reaction of a compound of the formula: ##STR4##wherein R³¹ is a ketal or acetal, with a lewis acid reagent; providedthat R⁴, taken as a whole, contains:

0 to 3 W groups substituted with 0 to 3 R²⁹ groups; and, in addition,

1 to 12 carbon atoms substituted with 0 to 3 R²² groups.

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR5## wherein: R², R⁴, R⁷,R²⁰ and R²¹ are as defined above.

which process comprises reaction of a compound of the formula: ##STR6##with a reducing reagent.

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR7## wherein: R², R⁴, R⁵,R²⁰ and R²¹ are as described above; and

Y¹ is a mono-, di- or unsubstituted amino group;

which process comprises reaction of a compound of the formula: ##STR8##with an amine reagent.

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR9## wherein: R², R⁴, R²⁰,R²¹ and Y¹ are as described above;

which process comprises reaction of a compound of the formula: ##STR10##with an oxidizing reagent.

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR11## wherein: R², R⁴, R²⁰,R²¹ and Y¹ are as described above;

which process comprises reaction of a compound of the formula: ##STR12##with a base.

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR13## wherein: R², R⁴, R⁷,R²⁰, R²¹ and Y¹ are as described above;

which process comprises reaction of a compound of the formula: ##STR14##with a reductive amination reagent.

DETAILED DESCRIPTION

General

The present invention is directed to methods of making the compositionsdescribed herein. Even though the compositions of the invention areprepared by any of the applicable techniques of organic synthesis, thepresent invention provides advantageous methods for accomplishing thepreparations.

Many conventional techniques are well known in the art and will not beelaborated here. However, many of the known techniques are elaborated in"Compendium of Organic Synthetic Methods" (John Wiley & Sons, New York),Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and LeroyWade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade,Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., "AdvancedOrganic Chemistry, Third Edition", (John Wiley & Sons, New York, 1985),"Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes", Barry M. Trost, Editor-in-Chief(Pergamon Press, New York, 1993 printing).

Generally, the reaction conditions such as temperature, reaction time,solvents, workup procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions.

The terms "treated", "treating", "treatment", and the like, meancontacting, mixing, reacting, allowing to react, bringing into contact,and other terms common in the art for indicating that one or morechemical entities is treated in such a manner as to convert it to one ormore other chemical entities. This means that "treating compound onewith compound two" is synonymous with "allowing compound one to reactwith compound two", "contacting compound one with compound two","reacting compound one with compound two", and other expressions commonin the art of organic synthesis for reasonably indicating that compoundone was "treated", "reacted", "allowed to react", etc., with compoundtwo.

"Treating" indicates the reasonable and usual manner in which organicchemicals are allowed to react. Normal concentrations (0.01M to 10M,typically 0.1M to 1M), temperatures (-100° C. to 250° C., typically -78°C. to 150° C., more typically -78° C. to 100° C., still more typically0° C. to 100° C.), solvents (aprotic or protic), reaction times(typically 10 seconds to 10 days, more typically 1 min. to 10 hours,still more typically 10 min. to 6 hours), reaction vessels (typicallyglass, plastic, metal), pressures, atmospheres (typically air for oxygenand water insensitive reactions or nitrogen or argon for oxygen or watersensitive), etc., are intended unless otherwise indicated. The knowledgeof similar reactions known in the art of organic synthesis are used inselecting the conditions and apparatus for "treating" in a givenprocess. In particular, one of ordinary skill in the art of organicsysnthesis selects conditions and apparatus reasonably expected tosuccessfully carry out the chemical reactions of the described processesbased on the knowledge in the art.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to-100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to -100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g. inert gasenvironments) are common in the art and will be applied when applicable.Workup typically consists of quenching any unreacted reagents followedby partition between a water/organic layer system (extraction) andseparating the layer containing the product. Each of the products of thefollowing processes is optionally separated, isolated, and/or purifiedprior to its use in subsecquent processes.

Embodiments

One aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR15## R¹ is a cyclichydroxy protecting group. A very large number of common protectinggroups (including cyclic hydroxy protecting groups) and correspondingchemical cleavage reactions are described in "Protective Groups inOrganic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., NewYork, 1991, ISBN 0-471-62301-6) ("Greene"). See also Kocienski, PhilipJ.; "Protecting Groups" (Georg Thieme Verlag Stuttgart, New York, 1994).In particular Chapter 1, Protecting Groups: An Overview, pages 1-20,Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, DiolProtecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups,pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184, andChapter 6, Amino Protecting Groups, pages 185-243. Typically, the cyclichydroxyprotecting groups are those commonly useful as 1,2-diolprotecting groups.

Typical 1,2-diol protecting groups (thus, generally where two OH groupsare taken together with the R¹ protecting functionality) are describedin Greene at pages 118-142 and include Cyclic Acetals and Ketals(Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,α-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,α-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene);Silyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene), andTetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, CyclicBoronates, Ethyl Boronate and Phenyl Boronate.

More typically, 1,2-diol protecting groups include those shown in TableA, or ayalic ketals or acetals. Still more typically, cyclic ketals andacetals.

                  TABLE A    ______________________________________     ##STR16##     ##STR17##    ______________________________________     ##STR18##    wherein R.sup.1a is C.sub.1 -C.sub.6 alkyl (as defined immediately below).

"Alkyl" as used herein, unless stated to the contrary, is C₁ -C₆hydrocarbon containing normal, secondary, tertiary or cyclic carbonatoms. Examples are methyl (Me, --CH₃), ethyl (Et, --CH₂ CH₃), 1-propyl(n-Pr, n-propyl, --CH₂ CH₂ CH₃), 2-propyl (i-Pr, i-propyl, --CH(CH₃)₂),1-butyl (n-Bu, n-butyl, --CH₂ CH₂ CH₂ CH₃), 2-methyl-1-propyl (i-Bu,i-butyl, --CH₂ CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, --CH(CH₃)CH₂ CH₃),2-methyl-2-propyl (t-Bu, t-butyl, --C(CH₃)₃), 1-pentyl (n-pentyl, --CH₂CH₂ CH₂ CH₂ CH₃), 2-pentyl (--CH(CH₃)CH₂ CH₂ CH₃), 3-pentyl (--CH(CH₂CH₃)₂), 2-methyl-2-butyl (--C(CH₃)₂ CH₂ CH₃), 3-methyl-2-butyl(--CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (--CH₂ CH₂ CH(CH₃)₂),2-methyl-1-butyl (--CH₂ CH(CH₃)CH₂ CH₃), 1-hexyl (--CH₂ CH₂ CH₂ CH₂ CH₂CH₃), 2-hexyl (--CH(CH₃)CH₂ CH₂ CH₂ CH₃), 3-hexyl (--CH(CH₂ CH₃)(CH₂ CH₂CH₃)), 2-methyl-2-pentyl (--C(CH₃)₂ CH₂ CH₂ CH₃), 3-methyl-2-pentyl(--CH(CH₃)CH(CH₃)CH₂ CH₃), 4-methyl-2-pentyl (--CH(CH₃)CH₂ CH(CH₃)₂),3-methyl-3-pentyl (--C(CH₃)(CH₂ CH₃)₂), 2-methyl-3-pentyl (--CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (--C(CH₃)₂ CH(CH₃)₂),3,3-dimethyl-2-butyl (--CH(CH₃)C(CH₃)₃). Typical alkyls are methyl,ethyl, 1-propyl, and 2-propyl.

R² is a carboxylic acid protecting group. Typical carboxylic acidprotecting groups are R²⁵ (described immediately below) or thosedescribed in Greene at pages 224-276.Those described in Greene includeEsters (Methyl); Substituted Methyl Esters (9-Fluorenylmethyl,Methoxymethyl, Methylthiomethyl, Tetrahydropyranyl, Tetrahydrofuranyl,Methoxyethoxymethyl, 2-(Trimethylsilyl)ethoxymethyl, Benzyloxymethyl,Phenacyl, p-Bromophenacyl, α-Methylphenacyl, p-Methoxyphenacyl,Carboxamidomethyl, N-Phthalimidomethyl); 2-Substituted Ethyl Esters(2,2,2-Trichloroethyl, 2-Haloethyl, ω-Chloroalkyl,2-(Trimethylsilyl)ethyl, 2-Methylthioethyl, 1,3-Dithianyl-2-methyl,2-(p-Nitrophenylsulfenyl)ethyl, 2-(p-Toluenesulfonyl)ethyl,2-(2'-Pyridyl)ethyl, 2-(Diphenylphosphino)ethyl, 1-Methyl-1-phenylethyl,t-Butyl, Cyclopentyl, Cyclohexyl, Allyl, 3-Buten-1-yl,4-(Trimethylsilyl)-2-buten-1-yl, Cinnamyl, α-Methylcinnamyl, Phenyl,p-(Methylmercapto)phenyl, Benzyl);

Substituted Benzyl Esters (Triphenylmethyl, Diphenylmethyl,Bis(o-nitrophenyl)methyl, 9-Anthrylmethyl, 2-(9,10-Dioxo)anthrylmethyl,5-Dibenzosuberyl, 1-Pyrenylmethyl, 2-(Trifluoromethyl)-6-chromylmethyl,2,4,6-Trimethylbenzyl, p-Bromobenzyl, o-Nitrobenzyl, p-Nitrobenzyl,p-Methoxybenzyl, 2,6-Dimethoxybenzyl, 4-(Methylsulfinyl)benzyl,4-Sulfobenzyl, Piperonyl, 4-Picolyl, p-poly-Benzyl); Silyl Esters(Trimethylsilyl, Triethylsilyl, t-Butyldimethylsilyl,i-Propyldimethylsilyl, Phenyldimethylsilyl, Di-t-butylmethylsilyl);Activated Esters (Thiols); Miscellaneous Derivatives (Oxazoles,2-Alkyl-1,3-oxazolines, 4-Alkyl-5-oxo-1,3-oxazolidines,5-Alkyl-4-oxo-1,3-dioxolanes, Ortho Esters, Phenyl Group,Pentaaminocobalt(III) Complex); Stannyl Esters (Triethylstannyl,Tri-n-butylstannyl); Amides (N,N-Dimethyl, Pyrrolidinyl, Piperidinyl,5,6-Dihydrophenanthridinyl, o-Nitroanilides, N-7-Nitroindolyl,N-8-Nitro-1,2,3,4-tetrahydroquinolyl, p-poly-Benzenesulfonamides); andHydrazides (Hydrazides, N-Phenyl, N,N'-Diisopropyl).

R²⁵ is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms,or alkynyl of 2 to 12 carbon atoms, any one of which alkyl, alkenyl, oralkynyl is substituted with 0-3 R²² groups (R²² is described below).More typically R²⁵ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6carbon atoms, or alkynyl of 2 to 6 carbon atoms, any one of which alkyl,alkenyl, or alkynyl is substituted with 0-3 R²² groups. Still moretypically, R²⁵ is alkyl of 1 to 8 carbon atoms substituted with 0-2 R²²groups. Even more typically, R²⁵ is alkyl of 1, 2, 3, 4, 5, 6, 7, or 8carbon atoms. Most typically R²⁵ is methyl, ethyl, 1-propyl or 2-propyl.

"Alkenyl" as used herein, unless stated to the contrary, is C₁ -C₆hydrocarbon containing normal, secondary, tertiary or cyclic carbonatoms. Examples are ethenyl (--CH═CH₂), 1-prop-1-enyl (--CH═CHCH₃),1-prop-2-enyl (--CH₂ CH═CH₂), 2-prop-1-enyl (--C(═CH₂)(CH₃)),1-but-1-enyl (--CH═CHCH₂ CH₃) 1-but-2-enyl (--CH₂ CH═CHCH₃),1-but-3-enyl (--CH₂ CH₂ CH═CH₂), 2-methyl-1-prop-1-enyl (--CH═C(CH₃)₂),2-methyl-1-prop-2-enyl (--CH₂ C(═CH₂)(CH₃)), 2-but-1-enyl (--C(═CH₂)CH₂CH₃), 2-but-2-enyl (--C(CH₃)═CHCH₃), 2-but-3-enyl (--CH(CH₃)CH═CH₂),1-pent-1-enyl (--C═CHCH₂ CH₂ CH₃), 1-pent-2-enyl (--CHCH═CHCH₂ CH₃),1-pent-3-enyl (--CHCH₂ CH═CHCH₃), 1-pent-4-enyl (--CHCH₂ CH₂ CH═CH₂),2-pent-1-enyl (--C(═CH₂)CH₂ CH₂ CH₃), 2-pent-2-enyl (--C(CH₃)═CH₂ CH₂CH₃), 2-pent-3-enyl (--CH(CH₃)CH═CHCH₃), 2-pent-4-enyl (--CH(CH₃)CH₂CH═CH₂) or 3-methyl-1-but-2-enyl (--CH₂ CH═C(CH₃)₂). More typically,alkenyl groups are of 2, 3 or 4 carbon atoms.

"Alkynyl" as used herein, unless stated to the contrary, is C₁ -C₆hydrocarbon containing normal, secondary, tertiary or cyclic carbonatoms. Examples are ethynyl (--C.tbd.CH), 1-prop-1-ynyl (--C.tbd.CCH₃),1-prop-2-ynyl (--CH₂ C.tbd.CH), 1-but-1-ynyl (--C.tbd.CCH₂ CH₃),1-but-2-ynyl (--CH₂ C.tbd.CCH₃), 1-but-3ynyl (--CH₂ CH₂ C.tbd.CH),2-but-3-ynyl (--CH(CH₃)C.tbd.CH), 1-pent-1-ynyl (--C.tbd.CCH₂ CH₂ CH₃),1-pent-2-ynyl (--CH₂ C.tbd.CCH₂ CH₃), 1-pent-3-ynyl (--CH₂ CH₂C.tbd.CCH₃) or 1-pent-4-ynyl (--CH₂ CH₂ CH₂ C.tbd.CH). More typically,alkynyl groups are of 2, 3 or 4 carbon atoms.

R³ is a hydroxy protecting group. Typical R³ hydroxy protecting groupsdescribed in Greene (pages 14-118) include Ethers (Methyl); SubstitutedMethyl Ethers (Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl,(Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl,p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl,t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl,2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl,Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl,Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl,1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl,4-Methoxytetrahydrothiopyranyl, 4-MethoxytetrahydropthiopyranylS,S-Dioxido, 1- (2-Chloro-4-methyl)phenyl!-4-methoxypiperidin-4-yl, 35,1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));Substituted Ethyl Ethers (1-Ethoxyethyl, 1-(2-Chloroethoxy)ethyl,1-Methyl-1-methoxyethyl, 1-Methyl-1-benzyloxyethyl,1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-Trichloroethyl,2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl, t-Butyl, Allyl,p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); SubstitutedBenzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl,p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl,p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido,Diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-Dibenzosuberyl,Triphenylmethyl, α-Naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl,Tri(p-methoxyphenyl)methyl, 4-(4'-Bromophenacyloxy)phenyldiphenylmethyl,4,4',4"-Tris(4,5-dichlorophthalimidophenyl)methyl,4,4',4"-Tris(levulinoyloxyphenyl)methyl,4,4',4"-Tris(benzoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl,1,1-Bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-Anthryl,9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido); Silyl Ethers(Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,Dimethylisopropylsilyl, Diethylisopropylsily, Dimethylthexylsilyl,t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl,Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl,t-Butylmethoxyphenylsilyl); Esters (Formate, Benzoylformate, Acetate,Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate,Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate,p-Chlorophenoxyacetate, p-poly-Phenylacetate, 3-Phenylpropionate,4-Oxopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate, Pivaloate,Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,2,4,6-Trimethylbenzoate (Mesitoate)); Carbonates (Methyl,9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl, Vinyl,Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl,o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate,4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate); Groups With AssistedCleavage (2-Iodobenzoate, 4-Azidobutyrate, 4-Niotro-4-methylpentanoate,o-(Dibromomethyl)benzoate, 2-Formylbenzenesulfonate,2-(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate,2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters(2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3tetramethylbutyl)phenoxyacetate,2,4-Bis(1,1-dimethylpropyl)phenoxyacetate, Chorodiphenylacetate,Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate),o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate, Nitrate,Alkyl N,N,N',N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate,Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); andSulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate,Tosylate).

More typically, R³ hydroxy protecting groups include substituted methylethers, substituted benzyl ethers, silyl ethers, and esters includingsulfonic acid esters, still more typically, trialkylsilyl ethers,tosylates, mesylates and acetates.

Each R²⁰ is independently H or an alkyl of 1 to 12 carbon atoms.Typically R²⁰ is H or alkyl of 1 to 6 carbon as described above. Stillmore typically, R²⁰ is H or methyl. More typically yet, R²⁰ is H.

This process embodiment comprises reaction of a compound of the formula:##STR19## with a dehydrating reagent. Typically the hydroxy group atposition 1 is eliminated without removing the cis-4,5-diol protectinggroup. The hydroxy group at position 1 is eliminated to form an olefinicbond between positions 1 and 6.

Typically the process comprises treating compound 4 with a suitabledehydrating agent, such as a mineral acid (HCl, H₂ SO₄) or SO₂ Cl₂. Moretypically, compound 4 is treated with SO₂ Cl₂, followed by an alkanol.Still more typically, compound 4 is treated with SO₂ Cl₂ in a suitablepolar, aprotic solvent, such as an amine to form an olefin. Moretypically yet, compound 4 is treated with SO₂ Cl₂ in pyridine/CH₂ Cl₂ ata temperature between -100° C. and 0° C., typically -100° C. and -10°C., more typically -78° C., to form compound 5.

In a typical embodiment, a solution of compound 4 and pyridine indichloromethane is cooled to -20° to -30° C. and treated portionwisewith sulfuryl chloride. After the exothermic reation subsided, theresulting slurry is quenched with ethanol, warmed to 0° C., and washedsuccessively with 16% sulfuric acid, water and 5% aqueous sodiumbicarbonate. A detailed example of this embodiment is provided asExample 4 below.

Optionally, the process of this embodiment further comprises purifyingor separating compound 5 from any other reaction products or othercontaminents such as other double bond isomers, halogenated sideproducts or starting materials and reagents by treatment with a noblemetal complex. Noble metals include gold, silver, platinum, palladium,iridium, rhenium, mercury, ruthenium and osmium. Typically, the noblemetal complex of this embodiment is a complex of platinum or palladium.More typically the complex is a palladium (0) complex, still moretypically, the complex is a tetrakis(triarylphosphine)palladium (0)complex.

In a typical embodiment the organic layer of the reaction contains amixture of olefin and halogenated products as well as starting material.It is concentrated in vacuo and ethyl acetate is added. The solution istreated with pyrrolidine and tetrakis(triphenylphosphine)palladium(0) atambient temperature, followed by washing with 16% sulfuric acid. Theorganic layer is filtered through a pad of silica gel and eluted withethyl acetate. The filtrate is concentrated in vacuo. The residue isdissolved in ethyl acetate at reflux and hexane is added. Upon cooling,the product crystallizes and is separated by filtration and washed with14% ethyl acetate in hexane. After drying in vacuo, 5 was obtained. Adetailed example of this embodiment is provided as Example 4 below.

In another example of this embodiment compound 5 is of the formula:##STR20##

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR21## wherein: R², R³ andR²⁰ are as defined above.

R⁴ is described below.

W is carbocycle or heterocycle wherein any one of which carbocycle orheterocycle is substituted with 0 to 3 R²⁹ groups (R²⁹ is describedbelow).

W is a carbocycle or heterocycle, with the proviso that each W isindependently substituted with 0 to 3 R²⁹ groups (R²⁹ is describedbelow). W carbocycles and heterocycles are stable chemical structures.Such structures are isolatable in measurable yield, with measurablepurity, from reaction mixtures at temperatures from -78° C. to 200° C.Each W is independently substituted with 0 to 3 R²⁹ groups. Typically, Wis a saturated, unsaturated or aromatic ring comprising a mono- orbicyclic carbocycle or heterocycle. More typically, W has 3 to 10 ringatoms, still more typically, 3 to 7 ring atoms, and ordinarily 3 to 6ring atoms. The W rings are saturated when containing 3 ring atoms,saturated or monounsaturated when containing 4 ring atoms, saturated, ormono- or diunsaturated when containing 5 ring atoms, and saturated,mono- or diunsaturated, or aromatic when containing 6 ring atoms.

When W is carbocyclic, it is typically a 3 to 7 carbon monocycle or a 7to 12 carbon atom bicycle. More typically, W monocyclic carbocycles have3 to 6 ring atoms, still more typically 5 or 6 ring atoms. W bicycliccarbocycles typically have 7 to 12 ring atoms arranged as a bicyclo4,5!, 5,5!, 5,6! or 6,6! system, still m typically, 9 or 10 ring atomsarranged as a bicyclo 5,6! or 6,6! system. Examples include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.

A W heterocycle is typically a monocycle having 3 to 7 ring members (2to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S)or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3heteroatoms selected from N, O, P, and S). More typically, Wheterocyclic monocycles have 3 to 6 ring atoms (2 to 5 carbon atoms and1 to 2 heteroatoms selected from N, O, and S), still more typically, 5or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selectedfrom N and S). W heterocyclic bicycles typically have 7 to 10 ring atoms(6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S)arranged as a bicyclo 4,5!, 5,5!, 5,6!, or 6,6! system, still moretypically, 9 to 10 ring at to 9 carbon atoms and 1 to 2 hetero atomsselected from N and S) arranged as a bicyclo 5,6! or 6,6! system.

"Heterocycle" as used herein includes by way of example and notlimitation these heterocycles described in Paquette, Leo A. ;"Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York,1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry ofHeterocyclic Compounds, A series of Monographs" (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and "J. Am. Chem. Soc. ", 82:5566 (1960).

Examples of heterocycles include by way of example and not limitationpyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidizedtetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thienyl, thianthrenyl,pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,and isatinoyl.

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

Typically W heterocycles are selected from pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, orpyrrolyl.

More typically, the heterocycle of W is bonded through a carbon atom ornitrogen atom thereof. Still more typically W heterocycles are bonded bya stable covalent bond through a carbon or nitrogen atom thereof. Stablecovalent bonds are chemically stable structures as described above.

W optionally is selected from the group consisting of: ##STR22## R⁵ is Hor R³.

R⁷ is H or an amino protecting group. R⁷ amino protecting groups aredescribed by Greene at pages 315-385. They include Carbamates (methyland ethyl, 9-fluorenylmethyl, 9(2-sulfo)fluoroenylmethyl,9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-buthyl-9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)!methyl,4-methoxyphenacyl); Substituted Ethyl (2,2,2-trichoroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and 4'-pyridyl)ethyl,2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl,p-nitrobenzyl, p-bromobenzyl, p-chorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); Groups WithAssisted Cleavage (2-methylthioethyl, 2-methylsulfonylethyl,2-(p-toluenesulfonyl)ethyl, 2-(1,3-dithianyl)!methyl,4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl,2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl); GroupsCapable of Photolytic Cleavage (m-nitrophenyl, 3,5-dimethoxybenzyl,o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives(phenothiazinyl-(10)-carbonyl, N'-p-toluenesulfonylaminocarbonyl,N'-phenylaminothiocarbonyl); Miscellaneous Carbamates (t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl,Isonicotinyl, p-(p'-Methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl,2,4,6-trimethylbenzyl); Amides (N-formyl, N-acetyl, N-choroacetyl,N-trichoroacetyl, N-trifluoroacetyl, N-phenylacetyl,N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide,N-benzoylphenylalanyl, N-benzoyl, N-p-phenylbenzoyl); Amides WithAssisted Cleavage (N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl,N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino)acetyl,N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine,N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl,4,5-diphenyl-3-oxazolin-2-one); Cyclic Imide Derivatives (N-phthalimide,N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridonyl); N-Alkyl and N-Aryl Amines (N-methyl, N-allyl,N- 2-(trimethylsilyl)ethoxy!methyl, N-3-acetoxypropyl,N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary AmmoniumSalts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl,N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl,N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene,N-ferrocenylmethyl, N-2-picolylamine N'-oxide), Imine Derivatives(N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenylidene,N-diphenylmethylene, N- (2-pyridyl)mesityl!methylene,N,(N',N'-dimethylaminomethylene, N,N'-isopropylidene,N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene,N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene); EnamineDerivatives (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)); N-Metal Derivatives(N-borane derivatives, N-diphenylborinic acid derivatives, N-phenyl(pentacarbonylchromium- or -tungsten)!carbenyl, N-copper or N-zincchelate); N-N Derivatives (N-nitro, N-nitroso, N-oxide); N-P Derivatives(N-diphenylphosphinyl, N-dimethylthiophosphinyl,N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl,N-diphenyl phosphoryl); N-Si Derivatives; N-S Derivatives; N-SulfenylDerivatives (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives(N-p-toluenesulfonyl, N-benzenesulfonyl,N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,N-2,4,6-trimethoxybenzenesulfonyl,N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl,N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl,N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,N-2,6-dimethoxy-4-methylbenzenesulfonyl,N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl,N-β-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl,N-4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonyl, N-benzylsulfonyl,N-trifluoromethylsulfonyl, N-phenacylsulfonyl). Typically, R⁷ is H or a--C(O)R²⁵ (R²⁵ is described above).

R⁸ is H or R². Typically R⁸ is H.

R⁹ is H or a thiol protecting group. R⁹ amino protecting groups aredescribed by Greene at pages 277-308. They includeThioethers (S-Benzyl,S-p-Methoxybenzyl, S-o- or p-Hydroxy- or Acetoxybenzyl, S-p-Nitrobenzyl,S-4-Picolyl, S-2-Picolyl N-Oxide, S-9-Anthrylmethyl,S-9-Fluorenylmethyl, S-Ferrocenylmethyl); S-Diphenylmethyl, SubstitutedS-Diphenylmethyl, and S-Triphenylmethyl Thioethers (S-Diphenylmethyl,S-Bis(4-methoxyphenyl)methyl, S-5-Dibenzosuberyl, S-Triphenylmethyl,S-Diphenyl-4-pyridylmethyl, S-Phenyl, S-2,4-Dinitrophenyl, S-t-Butyl,S-1-Adamantyl); Substituted S-Methyl Derivatives Monothio, Dithio, andAminothio Acetals (S-Methoxymethyl, S-Isobutoxymethyl,S-2-Tetrahydropyranyl, S-Benzylthiomethyl, S-Phenylthiomethyl,Thiazolidines, S-Acetamidomethyl, S-Trimethylacetamidomethyl,S-Benzamidomethyl, S-Acetyl-, S-Carboxy-, and S-Cyanomethyl);Substituted S-Ethyl Derivatives (S-2-Nitro-1-phenylethyl,S-2-(4'-Pyridyl)ethyl, S-2-Cyanoethyl, S-2,2-Bis(carboethoxy)ethyl,S-1-m-Nitrophenyl-2-benzoylethyl, S-2-Phenylsulfonylethyl,S-1-(4-Methylphenylsulfonyl)-2-methylprop-2-yl); Silyl Thioethers,Thioesters, (S-Acetyl Derivative, S-Benzoyl Derivative, S-N-(p-Biphenylyl)isopropoxy!carbonyl!-N-methyl-γ-aminobutyrate,S-N-(t-Butoxycarbonyl)-N-methyl-γ-aminobutyrate); ThiocarbonateDerivatives (S-2,2,2-Trichloroethoxycarbonyl, S-t-Butoxycarbonyl,S-Benzyloxycarbonyl, S-p-Methoxybenzyloxycarbonyl); ThiocarbamateDerivatives (S-(N-Ethyl), S-(N-Methoxymethyl); MiscellaneousDerivatives, Unsymmetrical Disulfides (S-Ethyl, S-t-Butyl, SubstitutedS-Phenyl); Sulfenyl Derivatives (S-Sulfonate, S-Sulfenylthiocarbonate,S-3-Nitro-2-pyridinesulfenyl Sulfide); Protection for Dithiols, DithioAcetals and Ketals (S,S'-Methylene, S,S'-Isopropylidene, andS,S'-Benzylidene, S,S'-p-Methoxybenzylidene); Protection for Sulfides(S-Methylsulfonium Salt, S-Benzyl- and S-4-Methoxybenzylsulfonium Salt,S-1-(4-Phthalimidobutyl)sulfonium Salt); S-P Derivatives(S-(Dimethylphosphino)thioyl, S-(Diphenylphosphino)thioyl);

Each R²¹ is independently R²⁰, Br, Cl, F, I CN,NO₂ or N₃. Typically, R²¹is Cl, F or R²⁰, more typically, R²⁰, still more typically, H.

Each R²² is independently F, Cl, Br, I, --CN, N₃, --NO₂, --OR⁵, --OR²⁰,--N(R²⁰)₂, --N(R²⁰)(R⁷), --N(R⁷)₂, --SR²⁰, --SR⁹, --S(O)R²⁰, --S(O)₂R²⁰, --S(O)OR²⁰, --S(O)OR⁸, --S(O)₂ OR²⁰, --S(O)₂ OR⁸, --C(O)OR²⁰,--C(O)OR⁸, --OC(O)R²⁰, --N(R²⁰)(C(O)R²⁰), --N(R⁷)(C(O)R²⁰),--N(R²⁰)(C(O)OR²⁰), --N(R⁷)(C(O)OR²⁰), --C(O)N(R²⁰)₂, --C(O)N(R⁷)(R²⁰),--C(O)N(R⁷)₂, --C(NR²⁰)(N(R²⁰)₂), --C(N(R⁷))(N(R²⁰)₂),--C(N(R²⁰))(N(R²⁰)(R⁷)), --C(N(R⁷))(N(R²⁰)(R.sup.7)),--C(N(R²⁰))(N(R⁷)₂), --C(N(R⁷))(N(R⁷)₂), --N(R²⁰)C(N(R²⁰))(N(R²⁰)₂),--N(R²⁰)C(N(R²⁰))(N(R²⁰)(R⁷)), --N(R²⁰)C(N(R⁷))(N(R²⁰)₂),--N(R⁷)C(N(R²⁰))(N(R²⁰)₂), --N(R⁷)C(N(R⁷))(N(R²⁰)₂),--N(R⁷)C(N(R²⁰))(N(R²⁰)(R⁷)), --N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)),--N(R²⁰)C(N(R²⁰))(N(R⁷)₂), --N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)),--N(R⁷)C(N(R²⁰))(R⁷)₂), --N(R²⁰)C(N(R⁷))(N(R⁷)₂),--N(R⁷)C(N(R⁷))(N(R⁷)₂), ═O, ═S, ═N(R²⁰), ═N(⁷) or W.

Typically R²² is F, Cl, Br, I, --CN, N₃, --NO₂, --OR⁵, --OR²⁰,--N(R²⁰)₂, --N(R²⁰)(R⁷), --N(R⁷)₂, --SR²⁰, --SR⁹, --S(O)R²⁰, --S(O)₂R²⁰, --S(O)OR²⁰, --S(O)OR⁸, --S(O)₂ OR²⁰, --S(O)₂ OR⁸, --C(O)OR²⁰,--C(O)OR⁸, ═O, ═S, ═N(R²⁰) or ═N(R⁷). More typically R²² is F, Cl, Br,--CN, N₃, --NO₂, --OR⁵, --OR²⁰, --N(R²⁰)₂, --N(R²⁰)(R⁷), --N(R⁷)₂,--C(O)OR²⁰, --C(O)OR⁸, or ═O. Still more typically R²² is F, Cl, Br,--CN, N₃, --NO₂, --OR²⁰, --N(R²⁰)₂, --C(O)OR²⁰ or ═O. More typically yetR²² is F, Cl, Br, --CN, --OH, --N(H)₂, --C(O)OR²⁰ or ═O.

Each R²³ is independently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to11 carbon atoms, or alkynyl of 2 to 11 carbon atoms. More typically R²³is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, oralkynyl of 2 to 8 carbon atoms, still more typically, R²³ is alkyl of 1to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6carbon atoms. More typically yet, R²³ is R²⁵.

Each R²⁴ is independently R²³ wherein each R²³ is substituted with 0 to3 R²² groups. Each of the typical embodiments of R²³ and R²² are typicalof R²⁴. More typically R²⁴ is substituted with 0, 1, 2, or 3 R²² groups.

R^(24a) is independently alkylene of 1 to 11 carbon atoms, alkenylene of2 to 11 carbon atoms, or alkynylene of 2-11 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R²²groups; compound. More typically R^(24a) is alkylene of 1 to 8 carbonatoms, alkenylene of 2 to 8 carbon atoms, or alkynylene of 2 to 8 carbonatoms, still more typically, R^(24a) is alkylene of 1 to 6 carbon atoms,alkenylene of 2 to 6 carbon atoms, or alkynylene of 2 to 6 carbon atoms.More typically yet, R^(24a) is --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --or --C(H)(CH₃)--.

Each R²⁸ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to12 carbon atoms, or alkynyl of 2 to 12 carbon atoms. More typically R²⁸is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, oralkynyl of 2 to 8 carbon atoms, still more typically, R²⁸ is alkyl of 1to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6carbon atoms. More typically yet, R²⁸ is R²⁵.

Each R²⁹ is independently R²² or R²⁸ wherein each R²⁸ is substitutedwith 0 to 3 R²² groups. Each of the typical embodiments of R²⁸ and R²²are typical of R²⁹. More typically R²⁹ is substituted with 0, 1, 2, or 3R²² groups.

Each R³⁰ is independently H, R²⁴, W or --R^(24a) W.

R⁴ is --C(R³⁰)₃, provided that R⁴, taken as a whole, contains 0 to 1 Wgroups (W is described above) substituted with 0 to 3 R²⁹ groups (R²⁹ isdescribed above); and, in addition, 1 to 12 carbon atoms substitutedwith 0 to 3 R²² groups (R²² is described above). Exemplary embodimentsof R⁴ are provided as U₁ embodiments in the documents cited in the"Brief Description of Related Art" above.

Typically one R³⁰ is H. More typically, one R³⁰ is H and the remainingtwo R³⁰ 's are independently R²⁴, W or --R^(24a) W. More typically yet,one R³⁰ is H, one R³⁰ is R²⁴ and the remaining R³⁰ is independently R²⁴,W or --R^(24a) W.

In one embodiment of R⁴, one R³⁰ is H, one R³⁰ is R²⁵ and one R³⁰ isR²⁴, W or --R^(24a) W. Typically, one R³⁰ is H and two R³⁰ 's are R²⁵.In another embodiment of R⁴, one R³⁰ is H, one R³⁰ is --R^(24a) W andone R³⁰ is R²⁴, W or --R^(24a) W. Typically, one R³⁰ is H, one R³⁰ is--R^(24a) W and one R³⁰ is R²⁴. In another embodiment, one R³⁰ is H andtwo R³⁰ 's are alkyl of 1 to 6 carbon atoms.

In another embodiment, R⁴ is: ##STR23## wherein R²⁶ is H, --CH₃, --CH₂CH₃, --CH₂ CH₂ CH₃, --OCH₃, --OAc (--O--C(O)CH₃), --OH, --NH₂, or --SH,typically H, --CH₃ or --CH₂ CH₃.

Typically each R⁴ (taken as a whole) contains 0-3 W groups each of whichis independently substituted with 0-3 R²⁹ groups; and each R⁴ (taken asa whole) in addition contains 1-12 carbon atoms, each carbon atom ofwhich is independently substituted with 0-3 R²² groups. More typicallyeach R⁴ contains 0, 1 or 2 such W groups, more typically yet, 0 or 1such W group.

In another embodiment, each R³⁰ group (taken as whole) of R⁴ is not soelectron withdrawing as to prevent the formation of compound 11. Lowry,T. H. and Richardson, K. S. "Mechanism and Theory in Organic Chemistry"(Harper & Row, 1976) at section 2.2, pages 60-71, and March, J."Advanced Organic Chemistry" (McGraw-Hill, 1977) at Chapter 9,Quantitative Treatments of the Effect of Structure on Reactivity", pages251-259, provide details of the electron withdrawing properties ofsubstitutent groups. In another embodiment, each R³⁰ group (taken aswhole) of R⁴ has a Hammett σ_(para) value of less than about 1,typically less than about 0.75, more typically less than about 0.5. Inanother embodiment, each R³⁰ group (taken as whole) of R⁴ has a Hammettσ_(para) value of -1.0 to 1.0, more typically -0.75 to 0.75, moretypically yet -0.5 to 0.5.

This process embodiment comprises reaction of a compound of the formula:##STR24## wherein R³¹ is a ketal or acetal, with a lewis acid reagent.Typically R³¹ is --C(R³⁰)₂ -- wherein R³⁰ is as described above.

Typically, compound 10 is reacted with a Lewis acid catalyst common inthe art, such as BF3·Et₂ O, TiCl₃, TMSOTf, SmI₂ (THF)₂, LiClO₄,Mg(ClO₄)₂, Ln(OTf)₃ (where Ln=Yb, Gd, Nd), Ti(Oi-Pr)₄, AlCl₃, AlBr₃,BeCl₂, CdCl₂, ZnCl₂, BF₃, BCl₃, BBr₃, GaCl₃, GaBr₃, TiCl₄, TiBr₄, ZrCl₄,SnCl₄, SnBr₄, SbCl₅, SbCl₃, BiCl₃, FeCl₃, UCl₄, ScCl₃, YCl₃, LaCl₃,CeCl₃, PrCl₃, NdCl₃, SmCl₃, EuCl₃, GdCl₃, TbCl₃, LuCl₃, DyCl₃, HoCl₃,ErCl₃, TmCl₃, YbCl₃, ZnI₂, Al(OPr^(i))₃, Al(acac)₃, ZnBr₂, or SnCl₄.Optionally, compound 10 is also treated with a reducing reagent. Typicalreducing reagents are of the form B(R³⁰)₃ such as BH₃. Optionallyreducing reagents of the form B(R³⁰)₃ are complexed with common solventssuch as diethylether and dimethylsulfide. A wide range of boranereducing reagents are known and will not be described in detail here.For example Brown, H. C. "Boranes in Organic Chemistry", (Cornell Univ.Press, Ithaca, N.Y., 1972) (Brown) provides a very large number ofexamples such as is found in Part Four, Selective Reductions, pages209-251, Part Five, Hydroboration, pages 255-297, and Part Six,Organoboranes, pages 301-446.

In a typical embodiment, compound 10 is treated with a lewis acid in anonprotic solvent. More typically, compound 10 is treated with a lewisacid and a reducing reagent in a nonprotic solvent.

In a typical embodiment, a solution of 10 in dichlorormethane is cooledand treated with borane-methyl sulfide complex and trimethylsilyltrifluoromethanesulfonate. 10% Aqueous sodium bicarbonate solution isslowly added. The mixture is warmed to ambient temperature and stirred.The organic layer is filtered and concentrated in vacuo to leavecompound 11. A detailed example of this embodiment is provided asExample 6 below.

In another example process of this embodiment compound 11 is of theformula: ##STR25##

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR26## wherein: R², R⁴, R⁷,R²⁰ and R²¹ are as defined above.

This process embodiment comprises reaction of a compound of the formula:##STR27## with a reducing reagent.

The azide of compound 30 is reduced to form compound 31.

Typically the process comprises treating compound 30 with a reducingagent to form compound 31. More typically the process comprises treatingcompound 30 with hydrogen gas and a catalyst (such as platinum on carbonor Lindlar's catalyst), or reducing reagents (typically a trisubstitutedphosphine such as trialkyl (P(R²⁵)₃) or triaryl phosphine (PW₃, e.g.triphenylphosphine). More typically still, the process comprisestreating compound 30 with triphenylphosphine and a base to form compound31.

Typically, compound 30 is disolved in a suitable polar, aprotic solventsuch as anhydrous acetonitrile. A solution of anhydroustriphenylphosphine in a suitable solvent such as anhydroustetrahydrofuran or a mixture of solvents is added dropwise. The mixtureis heated at reflux then concentrated in vacuo to leave compound 5. Adetailed example of this embodiment is provided as Example 9 below.

In another embodiment of this process compound 31 is of the formula:##STR28##

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR29## wherein: R², R⁴, R⁵,R²⁰ and R²¹ are as described above.

Y¹ is a mono-, di- or unsubstituted amino group. Typically Y¹ is of theformula --N(R³⁰)₂, a phthalimide or is a nitrogen containing heterocycle(defined above under W), more typically, Y¹ is a phthalimide, moretypically yet, a phthalimide salt.

This process embodiment comprises reaction of a compound of the formula:##STR30## with an amine reagent. Typically, the amine reagent is of theformula HY¹ or a salt of HY¹, such as, by way of example, NH₃ (McManns,et al., "Bull Soc. Chim. France" 850 (1947)), HY¹ generally (Moussevon,M., et al., "Synth. Commun." 3:177 (1973)) or phthalimide (Gabriel, etal., "Ber." 20:2224 (1887) or Gibson, et al., "Angew. Chem. Int.",7:919-930 (1968)).

The process comprises treating compound 40 with the amine reagent toproduce compound 32. More typically, compound 40 is treated with theamine reagent in a suitable polar a protic solvent (e.g. CH₃ CN, DMF orTHF). Optionally compound 40 is treated with the amine reagent and abase. Typical details of this process embodiment can be found in March,"Advanced Organic Chemistry" 4th. ed., pp 425-427.

In another embodiment of this process compound 41 is of the formula:##STR31##

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR32## wherein: R², R⁴, R²⁰,R²¹ and Y¹ are as described above;

This process embodiment comprises reaction of a compound of the formula:##STR33## with an oxidizing reagent. A wide range of suitable oxidationreagents are common in the art and will not be detailed here. Forexample House, H.O. "Modern Synthetic Reactions, Second Edition",Chapter 5, pages 259-273, describes the selective oxidation of alcohols.Typical reagents include CrO₃, Na₂ Cr₂ O₇, KMnO₄, PDC and PCC. Typicaldetails of this process embodiment can be found in Larock,"Comprehensive Organic Transformations", pp. 604-614; Corey et al. ,"Tetrahedron Lett." 31:2647-50 (1975); Ley et al., "Chem. Common" 1625(1987); Sweon, et al., "J. Org. Chem." 43:2480-2 (1978); and Martin, etal., "J. Org. Chem." 48:4155-56 (1983). Solvents typically include inertpolar solvents (e.g. CH₂ Cl₂, toluene or CH₃ CN).

In another embodiment of this process compound 51 is of the formula:##STR34##

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR35## wherein: R², R⁴, R²⁰,R²¹ and Y¹ are as described above;

This process embodiment comprises reaction of a compound of the formula:##STR36## with a base. Typically the base is a hindered amine orhindered alkoxide or the salts of either. More typically the base is ofthe formula NaOR²⁵, KOR²⁵ or NR²⁵ ₃, more typically yet, DBN, DBU ordiisopropyl ethyl amine.

In another embodiment of this process compound 61 is of the formula:##STR37##

Another aspect of the present invention is directed to processes for thepreparation of compounds of the formula: ##STR38## wherein: R², R⁴, R⁷ ₁R²⁰, R²¹ and Y¹ are as described above;

This process embodiment comprises reaction of a compound of the formula:##STR39## with a reductive amination reagent. Typical details of andreferences to this process embodiment can be found in Larock, op. cit.,pp. 421-425. Another typical description (NaCNBH₃ method) is Borch, "J.Am. Chem. Soc." 93:2897-2904 (1971).

Schemes 1 and 2 depict embodiments of the invention. Detaileddescriptions of the processes of Schemes 1 and 2 are provided in theExamples (below).

Additional individual process embodiments of the invention include anyone or sequential combination of processes AA, AB, AC, AD, AE, AF, AG,AH, AI, AJ, or AK of Schemes 1 and 2. "Sequential combination" as usedherein means more than one process wherein the individual processes areperformed one after the other in the order shown. Isolation, separation,purification is optionally performed prior to any of the individualprocesses.

Additional individual process embodiments of the invention include anyone or sequential combination of the processes of Example 1, Example 2,Example 3, Example 4, Example 5, Example 6, Example 7, Example 8,Example 9, Example 10, Example 11, Example 12 or Example 13. ##STR40##

Scheme 3 depicts the synthesis of the neuraminidase inhibitor 206 (R=H₂)by use of alternative nitrogen nucleophiles (March, "Advanced OrganicChemistry" 4th. ed., pp 425-427) to open the epoxide 201. Oxidation ofazidoalcohol 202 gives ketone 203 (Larock, "Comprehensive OrganicTransformations", pp. 604-614) in which the β-axial NR group isomerizesto the α-equatorial configuration 204. Reductive amination of the ketone204 (Larock, op. cit., pp. 421-425) gives the β-equatorial amine 205which is acetylated to afford 206. Cleavage of the R moiety (Greene,"Protective Groups in Organic Synthesis", pp. 218-287) gives theneuramidase inhibitor 206 (R=H₂).

Additional individual process embodiments of the invention include anyone or sequential combination of processes AL, AM, AN, AO, or AP ofScheme 3. ##STR41##

Modifications of each of the above schemes leads to various analogs ofthe specific exemplary materials produced above. The above citedcitations describing suitable methods of organic synthesis areapplicable to such modifications.

In each of the above exemplary schemes it may be advantageous toseparate reaction products from one another and/or from startingmaterials. The desired products of each step or series of steps isseparated and/or purified (hereinafter separated) to the desired degreeof homogeneity by the techniques common in the art. Typically suchseparations involve multiphase extraction, crystallization from asolvent or solvent mixture, distillation, sublimation, orchromatography. Chromatography can involve any number of methodsincluding, for example, size exclusion or ion exchange chromatography,high, medium, or low pressure liquid chromatography, small scale andpreparative thin or thick layer chromatography, as well as techniques ofsmall scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

STEREOISOMERS

The compounds of the invention are enriched or resolved optical isomersat any or all asymmetric atoms. For example, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diasteromeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention.

One or more of the following enumerated methods are used to prepare theenantiomerically enriched or pure isomers herein. The methods are listedin approximately their order of preference, i.e., one ordinarily shouldemploy stereospecific synthesis from chiral precursors beforechromatographic resolution before spontaneous crystallization.

Stereospecific synthesis is described in the examples. Methods of thistype conveniently are used when the appropriate chiral starting materialis available and reaction steps are chosen do not result in undesiredracemization at chiral sites. One advantage of stereospecific synthesisis that it does not produce undesired enantiomers that must be removedfrom the final product, thereby lowering overall synthetic yield. Ingeneral, those skilled in the art would understand what startingmaterials and reaction conditions should be used to obtain the desiredenantiomerically enriched or pure isomers by stereospecific synthesis.If an unexpected racemization occurs in a method thought to bestereospecific then one needs only to use one of the followingseparation methods to obtain the desired product.

If a suitable stereospecific synthesis cannot be empirically designed ordetermined with routine experimentation then those skilled in the artwould turn to other methods. One method of general utility ischromotographic resolution of enantiomers on chiral chromatographyresins. These resins are packed in columns, commonly called Pirklecolumns, and are commercially available. The columns contain a chiralstationary phase. The racemate is placed in solution and loaded onto thecolumn, and thereafter separated by HPLC. See for example, ProceedingsChromatographic Society--International Symposium on Chiral Separations,Sep. 3-4, 1987. Examples of chiral columns that could be used to screenfor the optimal separation technique would include Diacel Chriacel OD,Regis Pirkle Covalent Dphenylglycine, Regis Pirkle Type 1A, AstecCyclobond II, Astec Cyclobond III, Serva Chiral D-DL=Daltosil 100,Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate column,Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. Notall of these columns are likely to be effective with every racemicmixture. However, those skilled in the art understand that a certainamount of routine screening may be required to identify the mosteffective stationary phase. When using such columns it is desireable toemploy embodiments of the compounds of this invention in which thecharges are not neutralized, e.g., where acidic functionalities such ascarboxyl are not esterified or amidated.

Another method entails converting the enantiomers in the mixture todiasteriomers with chiral auxiliaries and then separting the conjugatesby ordinary column chromatography. This is a very suitable method,particularly when the embodiment contains free carboxyl, amino orhydroxyl that will form a salt or covalent bond to a chiral auxiliary.Chirally pure amino acids, organic acids or organosulfonic acids are allworthwhile exploring as chiral auxiliaries, all of which are well knownin the art. Salts with such auxiliaries can be formed, or they can becovalently (but reversibly) bonded to the functional group. For example,pure D or L amino acids can be used to amidate the carboxyl group ofembodiments of this invention and then separated by chromatography.

Enzymatic resolution is another method of potential value. In suchmethods one prepares covalent derivatives of the enantiomers in theracemic mixture, generally lower alkyl esters (for example of carboxyl),and then exposes the derivative to enzymatic cleavage, generallyhydrolysis. For this method to be successful an enzyme must be chosenthat is capable of stereospecific cleavage, so it is ftequentlynecessary to routinely screen several enzymes. If esters are to becleaved, then one selects a group of esterases, phosphatases, andlipases and determines their activity on the derivative. Typicalesterases are from liver, pancreas or other animal organs, and includeporcine liver esterase.

If the enatiomeric mixture separates from solution or a melt as aconglomerate, i.e., a mixture of enantiomerically-pure crystals, thenthe crystals can be mechanically separated, thereby producing theenantiomerically enriched preparation. This method, however, is notpractical for large scale preparations and is of no value for trueracemic compounds.

Asymmetric synthesis is another technique for achieving enantiomericenrichment. For example, a chiral protecting group is reacted with thegroup to be protected and the reaction mixture allowed to equilibrate.If the reaction is enantiomerically specific then the product will beenriched in that enantiomer.

Further guidance in the separation of enantiomeric mixtures can befound, by way of example and not limitation, in "Enantiomers, Racemates,and resolutions", Jean Jacques, Andre Collet, and Samuel H. Wilen(Krieger Publishing Company, Malabar, Fla., 1991, ISBN 0-89464-618-4).In particular, Part 2, "Resolution of Enantiomer Mixture", pages217-435; more particularly, section 4, "Resolution by DirectCrystallization", pages 217-251, section 5, "Formation and Separation ofDiastereomers", pages 251-369, section 6, "Crystallization-InducedAsymmetric Transformations", pages 369-378, and section 7, "ExperimentalAspects and Art of Resolutions", pages 378-435; still more particularly,section 5.1.4, "Resolution of Alcohols, Transformation of Alcohols intoSalt-Forming Derivatives", pages 263-266, section 5.2.3, "CovalentDerivatives of Alcohols, Thiols, and Phenols", pages 332-335, section5.1.1, "Resolution of Acids", pages 257-259, section 5.1.2, "Resolutionof Bases", pages 259-260, section 5.1.3, "Resolution of Amino Acids",page 261-263, section 5.2.1, "Covalent Derivatives of Acids", page 329,section 5.2.2, "Covalent Derivatives of Amines", pages 330-331, section5.2.4, "Covalent Derivatives of Aldehydes, Ketones, and Sulfoxides",pages 335-339, and section 5.2.7, "Chromatographic Behavior of CovalentDiastereomers", pages 348-354, are cited as examples of the skill of theart.

SALTS AND HYDRATES

The compositions of this invention optionally comprise salts of thecompounds herein, for example, Na⁺, Li⁺, K⁺, Ca⁺⁺ and Mg⁺⁺. Such saltsmay include those derived by combination of appropriate cations such asalkali and alkaline earth metal ions or ammonium and quaternary aminoions with an acid anion moiety. Monovalent salts are preferred if awater soluble salt is desired.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂ SO₄, H₃ PO₄ or organic sulfonicacids, to basic centers, typically amines. Finally, it is to beunderstood that the compositions herein comprise compounds of theinvention in their un-ionized, as well as zwitterionic form, andcombinations with stoiochimetric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids. Any of the amino acidsdescribed above are suitable, especially the naturally-occuring aminoacids found as protein components, although the amino acid typically isone bearing a side chain with a basic or acidic group, e.g., lysine,arginine or glutamic acid, or a neutral group such as glycine, serine,threonine, alanine, isoleucine, or leucine.

ADDITIONAL USES FOR THE COMPOUNDS OF THIS INVENTION

The compounds of the invention are polyfunctional. As such theyrepresent a unique class of monomers for the synthesis of polymers. Byway of example and not limitation, the polymers prepared from thecompounds of this invention include polyamides, polyesters and mixedpolyester-polyamides.

The present compounds are used as monomers to provide access to polymershaving unique pendent functionalities. The compounds of this inventionare useful as comonomers with monomers which do not fall within thescope of the invention. Polymers of the compounds of this invention willhave utility as cation exchange agents (polyesters or polyamides) in thepreparation of molecular sieves (polyamides), textiles, fibers, films,formed articles and the like. Polymers are prepared by any conventionalmethod, for example, by cross-linking an --OH or --NH₂ group of thecompounds of the invention with a diacid comonomer. The preparation ofthese polymers from the compounds of the invention is conventional perse.

The compounds of the invention are also useful as a unique class ofpolyfunctional surfactants. Particularly when R⁴ or R² do not containhydrophilic substituents and are, for example, alkyl, the compounds havethe properties of bi-functional surfactants. As such they have usefulsurfactant, surface coating, emulsion modifying, rheology modifying andsurface wetting properties.

As polyfunctional compounds with defined geometry and carryingsimultaneously polar and non-polar moieties, the compounds of theinvention are useful as a unique class of phase transfer agents. By wayof example and not limitation, the compounds of the invention are usefulin phase transfer catalysis and liquid/liquid ion extraction (LIX).

The compounds of the invention optionally contain asymmetric carbonatoms. As such, they are a unique class of chiral auxiliaries for use inthe synthesis or resolution of other optically active materials. Forexample, a racemic mixture of carboxylic acids can be resolved into itscomponent enantiomers by: 1) forming a mixture of diastereomeric estersor amides with a compound of the invention containing an --OH or --NH₂group; 2) separating the diastereomers; and 3) hydrolyzing the esterstructure. Further, such a method can be used to resolve the compoundsof the invention themselves if optically active acids are used insteadof racemic starting materials.

The compounds of this invention are useful as linkers or spacers inpreparing affinity absorption matrices, immobilized enzymes for processcontrol, or immunoassay reagents. The compounds herein contain amultiplicity of functional groups that are suitable as sites forcross-linking desired substances. For example, it is conventional tolink affinity reagents such as hormones, peptides, antibodies, drugs,and the like to insoluble substrates. These insolublized reagents areemployed in known fashion to absorb binding partners for the affinityreagents from manufactured preparations, diagnostic samples and otherimpure mixtures. Similarly, immobilized enzymes are used to performcatalytic conversions with facile recovery of enzyme. Bifunctionalcompounds are commonly used to link analytes to detectable groups inpreparing diagnostic reagents.

Many functional groups in the compounds of this invention are suitablefor use in cross-linking. For example, --OH and --NH₂ groups. Suitableprotection of reactive groups will be used where necessary whileassembling the cross-linked reagent to prevent polymerization of thebifunctional compound of this invention. In general, the compounds hereare used by linking them through hydroxyl or amino groups to carboxylicor phosphonic acid groups of the first linked partner, then covalentlybonding to the other binding partner through another --OH or --NH₂group. For example a first binding partner such as a steroid hormone isreacted to form an amide bond with the --NH₂ group of a compound of thisinvention and then this conjugate is cross-linked through a hydroxyl tocyanogen bromide activated Sepaharose, whereby immobilized steroid isobtained. Other chemistries for conjugation are well known. See forexample Maggio, "Enzyme-Immunoassay" (CRC, 1988, pp 71-135) andreferences cited therein.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake the compounds and compositions of the invention and are notintended to limit the scope of what the inventors regard as theirinvention. Efforts have been made to insure accuracy with respect tonumbers used (e.g., amounts, temperatures, etc.), but some experimentalerrors and deviations should be taken into account. Unless indicatedotherwise, parts are parts by weight, temperature is in degreesCentigrade, and pressure is at or near atmospheric.

EXAMPLES Example 1

Lactone 100:A solution of quinic acid (20 kg, 104 mol; α!_(D) -43.7°(c=1.12, water); "Merck Index 11th ed"., 8071: α!_(D) -42° to -44°(water)), 2,2-dimethoxypropane (38.0 kg, 365 mol) and p-toluenesulfonicacid monohydrate (0.200 kg, 1.05 mol) in acetone (80 kg) was heated atreflux for two hours. The reaction was quenched by addition of 21%sodium ethoxide in ethanol (0.340 kg, 1.05 mol) and most of the solventwas distilled in vacuo. The residue was partitioned between ethylacetate (108 kg) and water (30 kg). The aqueous layer was back-extractedwith ethyl acetate (13 kg) and the combined organic layers were washedwith 5% aqueous sodium bicarbonate (14 kg). Most of the ethyl acetatewas distilled in vacuo to leave a pale yellow solid residue of 100 whichwas used directly in the next step.

Example 2

Hydroxy ester 101:A solution of the crude lactone 100 (from 104 mol(-)-quinic acid) in absolute ethanol (70 kg) was treated with 20% sodiumethoxide in ethanol (0.340kg, 1.05 mol). After two hours at roomtemperature, acetic acid (0.072 kg, 1.2 mol) was added and the solventwas distilled in vacuo. Ethyl acetate (36 kg) was added and thedistillation continued to near dryness. The tan solid residue composedof a ca. 5:1 mixture of 101:100 was dissolved in ethyl acetate (9 kg) atreflux and hexane (9 kg) was added. Upon cooling, a white crystallinesolid formed which was isolated by filtration to afford a ca. 6.5:1mixture of 101:100 (19.0 kg, 70% yield).

Example 3

Mesyl ester 102: A solution of a ca. 6.5:1 mixture (18.7 kg, ca. 72 mol)of hydroxy ester 101 and lactone 100 in dichloromethane (77 kg) wascooled to 0°-10° C. and treated with methanesulfonyl chloride (8.23 kg,71.8 mol), followed by slow addition of triethylamine (10.1 kg, 100mol). An additional portion of methanesulfonyl chloride (0.84 kg, 7.3mol) was added. After one hour, water (10 kg) and 3% hydrochloric acid(11 kg) were added. The layers were separated and the organic layer waswashed with water (9 kg), then distilled in vacuo to leave a semi-solidresidue composed of a ca. 6.5:1 mixture of mesyl ester 102 and mesyllactone 103. The residue was dissolved in ethyl acetate (11 kg) andcooled to -10° to -20° C. for two hours. Mesyl lactone 103 crystallizedand was separated by filtration and washed with cold ethyl acetae (11kg). The filtrate was concentrated to afford mesyl ester 102 as anorange resin (20.5 kg, 84.3% yield).

Example 4

Mesyl acetonide 104: A solution of mesyl ester 102 (10.3 kg, 30.4 mol)and pyridine (10.4 kg, 183 mol) in dichloromethane (63 kg) was cooled to-20° to -30° C. and treated portionwise with sulfuryl chloride (6.22 kg,46 mol). After the exothermic reaction subsided, the resulting slurrywas quenched with ethanol (2.4 kg), warmed to 0° C., and washedsuccessively with 16% sulfuric acid (35 kg), water (15 kg) and 5%aqueous sodium bicarbonate (1 kg). The organic layer containing a ca.4:1:1 mixture of 104:105:106 was concentrated in vacuo and ethyl acetate(14 kg) was added. The allylic mesylate 105 was selectively removed bytreatment of the ethyl acetate solution with pyrrolidine (2.27 kg, 31.9mol) and tetrakis(triphenylphosphine)palladium(0) (0.0704 kg, 0.061mol)at ambient temperature for five hours, followed by washing with 16%sulfuric acid (48 kg). The organic layer was filtered through a pad ofsilica gel (11 kg) and eluted with ethyl acetate (42 kg). The filtratewas concentrated in vacuo to leave a thick orange oil composed of a ca.4:1 mixture of 104:106. The residue was dissolved in ethyl acetate (5.3kg) at reflux and hexane (5.3 kg) was added. Upon cooling, mesylacetonide 104 crystallized and was separated by filtration and washedwith 14% ethyl acetate in hexane (2.1 kg). After drying in vacuo, 104was obtained as pale yellow needles (4.28 kg, 43.4% yield), mp 102°-3°C.

Example 5

Pentyl ketal 107: A solution of acetonide 104 (8.9 kg, 27.8 mol),3-pentanone (24 kg, 279 mol) and 70% perchloric acid (0.056 kg, 0.39mol) was stirred for 18 hours. The volatiles were distilled in vacuo atambient temperature and fresh 3-pentanone (30 kg, 348 mol) was addedgradually as the distillation progressed. The reaction mixture wasfiltered, toluene (18 kg) was added, and the resulting solution waswashed successively with 6% aqueous sodium bicarbonate (19 kg), water(18 kg) and brine (24 kg). The organic layer was concentrated in vacuoand toluene (28 kg) was added gradually as the distillation progressed.When no more distilled, the residual orange oil was composed of pentylketal 107 (9.7 kg, 100% yield) and toluene (ca. 2 kg).

Example 6

Pentyl ether 108: A solution of ketal 107 (8.6 kg, 25 mol) indichloromethane (90 kg) was cooled to -30° to -20° C. and treated withboranemethyl sulfide complex (2.1 kg, 27.5 mol) and trimethylsilyltrifluoromethanesulfonate (7.2 kg, 32.5 mol). After one hour, 10%aqueous sodium bicarbonate solution (40 kg) was slowly added. Themixture was warmed to ambient temperature and stirred for 12 hours. Theorganic layer was filtered and concentrated in vacuo to leave a ca. 8:1mixture of 108:109 as a gray waxy solid (7.8 kg, 90% yield).

Example 7

Epoxide 110: A ca. 8:1 mixture of isomeric pentyl ethers 108:109 (7.8kg, 22.3 mol) in ethanol (26 kg) was treated with a solution ofpotassium hydrogen carbonate (3.52 kg, 35 mol) in water (22 kg). Afterheating at 55°-65° C. for two hours, the solution was cooled and twiceextracted with hexanes (31 kg, then 22 kg). Unreacted 109 remained inthe aqueous ethanol layer. The combined hexane extracts were filteredand concentrated in vacuo to leave epoxide 110 as a flocculent whitecrystalline solid (3.8 kg, 60% yield), mp=54.6° C.

Example 8

Hydroxy azide 111: A mixture of epoxide 110 (548 g, 2.0 mol), sodiumazide (156 g, 2.4 mol) and ammonium chloride (128.4 g, 2.4 mol) in water(0.265 L) and ethanol (1.065 L) was heated at 70°-75° C. for eighthours. Aqueous sodium bicarbonate (0.42 L of 8% solution) was added andthe ethanol was distilled in vacuo. The aqueous residue was extractedwith ethyl acetate (1 L) and the extract was washed with water (0.5 L).The water wash was back-extracted with ethyl acetate (0.5 L). Thecombined organic extracts were washed with brine (0.5 L), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to leave aca. 10:1 mixture of isomeric hydroxy azides 111:112 (608 g, 102% yield)as a dark brown oil.

Example 9

Aziridine 113: A ca. 10:1 mixture of hydroxy azides 111:112 (608 g, 2.0mol) was three times co-evaporated in vacuo from anhydrous acetonitrile(3×0.3 L) and then dissolved in anhydrous acetonitrile (1 L). A solutionof anhydrous triphenylphosphine (483 g, 1.84 mol) in anhydroustetrahydrofuran (0.1 L) and anhydrous acetonitrile (0.92 L) was addeddropwise over two hours. The mixture was heated at reflux for six hoursthen concentrated in vacuo to leave a golden paste composed of aziridine113, triphenylphosphine oxide and traces of triphenylphosphine. Thepaste was triturated with diethyl ether (0.35 L). Most of the insolubletriphenylphosphine oxide was removed by filtration and washed withdiethyl ether (1.5 L). The filtrate was concentrated in vacuo to leave adark brown oil which was dissolved in 20% aqueous methanol and extractedthree times with hexanes (3×1 L) to remove triphenylphosphine. Thehexane extracts were back-extracted with 20% aqueous methanol (0.5 L)and the combined aqueous methanol layers were concentrated in vacuo. Theresidue was twice co-evaporated in vacuo from anhydrous acetonitrile(2×0.5 L) to leave a dark brown oil composed of aziridene 113 (490 g,96.8 % yield) and triphenylphosphine oxide (ca. 108 g) which was useddirectly in the next step.

Example 10

Acetamido azide 115: A mixture of aziridine 113 (490 g, 1.93 mol) andtriphenylphosphine oxide (ca. 108 g), sodium azide (151 g, 2.33 mol) andammonium chloride (125 g, 2.33 mol) in dimethylformamide (1.3 L) washeated at 80°-°-85° C. for five hours. Sodium bicarbonate (32.8 g, 0.39mol) and water (0.66 L) were added. The amino azide 114 was isolatedfrom the reaction mixture by six extractions with hexanes (6×1 L). Thecombined hexane extracts were concentrated in vacuo to ca. 4.5 L totalvolume and dichloromethane (1.04 L) was added. Aqueous sodiumbicarbonate (4.2 L of 8% solution, 3.88 mol) was added, followed byacetic anhydride (198 g, 1.94 mol). After stirring for one hour atambient temperature, the aqueous layer was discarded. The organic phaseswere concentrated in vacuo to 1.74 kg total weight and dissolved withethyl acetate (0.209 L) at reflux. Upon cooling, acetamido azide 115crystallized and was isolated by filtration. After washing with cold 15%ethyl acetate in hexane (1 L) and drying in vacuo at ambienttemperature, pure 115 was obtained as off-white crystals (361 g, 55%yield), mp 126°-132° C.

Example 11

Acetamido amine 116: A mixture of azide 115 (549 g, 1.62 mol) andLindlar catalyst (50 g) in abs. ethanol (3.25 L) was stirred foreighteen hours while hydrogen (1 atm.) was bubbled through the mixture.Filtration through Celite and concentration of the filtratein vacuoafforded 116 as a foam which solidified on standing (496 g, 98% yield).

Example 12

Phosphate salt of 116: A solution of acetamido amine 116 (5.02 g, 16.1mmol) in acetone (75 mL) at reflux was treated with 85% phosphoric acid(1.85 g, 16.1 mmol) in abs. ethanol (25 mL). Crystallization commencedimmediately and after cooling to 0° C. for 12 hours the precipitate wascollected by filtration to afford 116·H₃ PO₄ as long colorless needles(4.94 g, 75% yield; α!_(D) -39.9° (c=1, water)), mp 203°-4° C.

Example 13

Hydrochloride salt of 116: A solution of acetamido amine 116 (2.8 g,8.96 mmol) in abs. ethanol (9 mL) was treated with 2.08M hydrogenchloride in ethanol (8.6 mL, 17.9 mmol). Most of the ethanol wasevaporated in vacuo and the oily residue was stirred with ethyl acetate(20 mL) until solid formed. Hexanes (20 mL) were gradually added to thestirred mixture. After one hour at ambient temperature, the solid wascollected by filtration, washed with diethyl ether and dried in vacuo.This afforded 116·HCl as an off-white solid (2.54 g, 81% yield; α!_(D)-43° (c=0.4, water)), mp206° C.

All literature and patent citations above are hereby expresslyincorporated by reference in their entirety at the locations of theircitation. Specifically cited sections or pages of the above cited worksare incorporated by reference with specificity.

Whenever a compound described herein is substituted with more than oneof the same designated group, such as, by was of example and notlimitation, "R⁷ ", "R⁸ ", "R⁹ ", "R²⁰ ", or "R²² " , then it will beunderstood that each of the groups may be the same or different, i.e.,each group is independently selected. So for example, the phrase "R²²is" is synonymous with the phrase "each R²² is independently".

The invention has been described in detail sufficient to allow one ofordinary skill in the art to make and use the subject matter of thefollowing claims. It is apparent that certain modifications of themethods and compositions of the following claims can be made within thescope and spirit of the invention.

What is claimed is:
 1. A process for preparation of compounds of theformula: ##STR42## wherein: R² is a carboxylic acid protecting group;R³is a hydroxy protecting group; R⁴ is --C(R³⁰)₃ ; R⁵ is H or R³ ; R⁷ is Hor an amino protecting group; R⁸ is H or R² ; R⁹ is H or a thiolprotecting group; each R²⁰ is independently H or an alkyl of 1 to 12carbon atoms; each R²¹ is independently R²⁰, Br, Cl, F, I, CN, NO₂ or N₃; each R²² is independently F, Cl, Br, I, --CN, N₃, --NO₂, --OR⁵,--OR²⁰, --N(R²⁰)₂, --N(R²⁰)(R⁷), --N(R⁷)₂, --SR²⁰, --SR⁹, --S(O)R²⁰,--S(O)₂ R²⁰, --S(O)OR²⁰, --S(O)OR⁸, --S(O)₂ OR²⁰, --S(O)₂ OR⁸,--C(O)OR²⁰, --C(O)OR⁸, --OC(O)R²⁰, --N(R²⁰)(C(O)R²⁰), --N(R⁷)(C(O)R²⁰),--N(R²⁰)(C(O)OR²⁰), --N(R⁷)(C(O)OR²⁰), --C(O)N(R²⁰)₂, --C(O)N(R⁷)(R²⁰),--C(O)N(R⁷)₂, --C(NR²⁰)(N(R²⁰)₂), --C(N(R⁷))(N(R²⁰)₂),--C(N(R²⁰))(N(R²⁰)(R⁷)), --C(N(R⁷))(N(R²⁰)(R.sup.7)),--C(N(R²⁰))(N(R⁷)₂), --C(N(R⁷))(N(R⁷)₂), --N(R²⁰)C(N(R²⁰))(N(R²⁰)₂),--N(R²⁰)C(N(R²⁰))(N(R²⁰)(R⁷)), --N(R²⁰)C(N(R⁷))(N(R²⁰)₂),--N(R⁷)C(N(R²⁰))(N(R²⁰)₂), --N(R⁷)C(N(R⁷))(N(R²⁰)₂),--N(R⁷)C(N(R²⁰))(N(R²⁰)(R⁷)), --N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)),--N(R²⁰)C(N(R²⁰))(N(R⁷)₂), --N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)),--N(R⁷)C(N(R²⁰))(N(R⁷)₂), --N(R²⁰)C(N(R⁷))(N(R⁷)₂),--N(R⁷)C(N(R⁷))(N(R⁷)₂), ═O, ═S, ═N(R²⁰), ═N(R⁷) or W; R²³ isindependently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbonatoms, or alkynyl of 2 to 11 carbon-atoms; R²⁴ is independently R²³wherein each R²³ is substituted with 0 to 3 R²² groups; R^(24a) isindependently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11carbon atoms, or alkynylene of 2-11 carbon atoms any one of whichalkylene, alkenylene or alkynylene is substituted with 0-3 R²² groups;compound; R²⁸ is independently alkyl of 1 to 12 carbon atoms, alkenyl of2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms; R²⁹ isindependently R²² or R²⁸ wherein each R²⁸ is substituted with 0 to 3 R²²groups; each R³⁰ is independently H, R²⁴, W or R^(24a) -W; and W iscarbocycle or heterocycle wherein any one of which carbocycle orheterocycle is substituted with 0 to 3 R²⁹ groups;which processcomprises reaction of a compound of the formula: ##STR43## wherein R³¹is a ketal or acetal, with a lewis acid reagent; provided that R⁴, takenas a whole, contains: 0to 3 W groups substituted with 0 to 3 R²⁹ groups;and 1 to 12 carbon atoms substituted with 0 to 3 R²² groups.
 2. Theprocess of claim 1 which further comprises treating compound 10 with areducing reagent.
 3. The process of claim 1 wherein compound 11 is ofthe formula: ##STR44##